KR0125155B1 - Phthalimide compounds and method of producing same - Google Patents
Phthalimide compounds and method of producing sameInfo
- Publication number
- KR0125155B1 KR0125155B1 KR1019930702259A KR930702259A KR0125155B1 KR 0125155 B1 KR0125155 B1 KR 0125155B1 KR 1019930702259 A KR1019930702259 A KR 1019930702259A KR 930702259 A KR930702259 A KR 930702259A KR 0125155 B1 KR0125155 B1 KR 0125155B1
- Authority
- KR
- South Korea
- Prior art keywords
- phthalimide
- acid
- acid addition
- piperidinylmethyl
- oxy
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
본 발명은, 다음식( I )The present invention is the following formula (I)
(식중, Y는 -CH2-CH2- 또는 -CH=CH-이다.)Wherein Y is -CH 2 -CH 2 -or -CH = CH-.
로 표시되는 프탈이미드 화합물 및 그 산부가염 및 그들의 제조방법에 관한 것이다.It relates to a phthalimide compound, acid addition salt thereof, and a method for producing the same.
본 발명은 의약품, 특히 히스타민 H2수용체 길항작용에 의거한 항궤양제의 제조중간체로서 유용한 화합물인 상기의 식(Ｉ)로 표시되는 프탈이미드 화합물 및 그 산부가염을 제공하는 것이다. 특히 프탈이미드 화합물의 산부가염은, 재결정법에 의해 용이하게 정제가능하고, 그에 의해서 본 발명의 프탈이미드 화합물 및 그 산부가염으로부터 유도되는 항궤양제의 순도의 향상에 기여할 수 있다고 하는 효과를 나타낸다.The present invention provides a phthalimide compound represented by the above formula (I) and an acid addition salt thereof, which are compounds useful as intermediates for the preparation of pharmaceuticals, in particular, anti-ulcer agents based on histamine H 2 receptor antagonism. In particular, the acid addition salt of the phthalimide compound can be easily purified by a recrystallization method, thereby contributing to the improvement of the purity of the phthalimide compound of the present invention and the antiulcer agent derived from the acid addition salt thereof. Indicates.
Description
[발명의 명칭][Name of invention]
프탈아미드 화합물 및 그 제조방법Phthalamide compound and preparation method thereof
[발명의 상세한 설명]Detailed description of the invention
기술분야Technical Field
본 발명은, 다음식(I)The present invention is the following formula (I)
(식중, Y는 -CH2-CH2- 또는 -CH=CH-이다.)Wherein Y is -CH 2 -CH 2 -or -CH = CH-.
로 표시되는 프탈이미드 화합물 및 그 산부가염 및 그들의 제조방법에 관한 것이다. 상기 식(I)에서 표시되는 프탈이미드 화합물 및 그 산부가염은, 의약품 특히 히타민 H2수용체 길항작용에 의거한 항궤양제의 제조중간체로서 유용한 화합물It relates to a phthalimide compound, acid addition salt thereof, and a method for producing the same. The phthalimide compound represented by the formula (I) and acid addition salts thereof are compounds useful as pharmaceutical intermediates for the preparation of anti-ulcer drugs based on medicaments, in particular, the amine H 2 receptor antagonism.
(배경기술)(Background)
종래, 히스타민 H2수용체 길항작용에 의거한 항소화성 궤양제는, 일본국 특개소 6l-85365호 공보에 다음식(Ⅶ)Conventionally, an anti-extinguishing ulcer based on histamine H 2 receptor antagonism is described in Japanese Patent Application Laid-Open No. 6l-85365.
(식중, Z는 -CH=CH-이다.)(Wherein Z is -CH = CH-).
로 표시되는 화합물이 개시되고, 또, 동특개소 63-225371호 공보에 다음식(Ⅷ)The compound represented by this is disclosed, and the following formula is disclosed by the same patent publication 63-225371.
(식중, Y는 -CH2-CH2- 또는 -CH=CH-이다.)Wherein Y is -CH 2 -CH 2 -or -CH = CH-.
로 표시되는 화합물이 개시되어 있다. 이들의 화합물의 공통의 중간체로서 다음식(Ⅸ)The compound represented by is disclosed. As a common intermediate of these compounds
(식중, Y는 -CH2-CH2- 또는 -CH=CH-이다.)Wherein Y is -CH 2 -CH 2 -or -CH = CH-.
로 표시되는 화합물이 사용되고 있다. 이 화합물의 종래의 합성법은 다음식(X)The compound represented by is used. The conventional synthesis method of this compound is represented by the following formula (X)
로 표시되는 화합물 및 다음식(XI)Compound represented by the following formula (XI)
HO/＼Y/＼NH2(XI)HO / ＼Y / ＼NH 2 (XI)
(식중, Y는 -CH2CH2- 또는 -CH=CH-이다.)Wherein Y is -CH 2 CH 2 -or -CH = CH-.
로 표시되는 화합물의 양자를 반응시키는데 따른 것이다. 그러나, 이 합성법을 사용한 경우, 원료인 상기 식(X) 및 상기 식(XI)로 표시되는 화합물의 공업적 입수가 불가능하고, 제조하면 고가가 된다고 하는 문제가 있다. 또 상기 식(X) 및 상기 식(XI)로 표시되는 화합물의 반응에 의한 상기의 식(IX)로 표시되는 화합물의 제조에 있어서는 부생성물이나 분해물이 많고, 그때문에 정제에 부하가 걸리는 등 상기의 중간체(IX)로의 유도가 매우 번잡하고, 공업화하는데는 문제가 많은 방법이다.It is for reacting both of the compounds represented by. However, when this synthesis method is used, there is a problem that industrial availability of the compounds represented by the above formulas (X) and (XI) as raw materials is impossible and expensive if produced. In the preparation of the compound represented by the formula (IX) by the reaction of the compound represented by the formula (X) and the formula (XI), there are many by-products and decomposition products, and thus, the purification is burdened. Is very complicated to introduce into the intermediate (IX) and is a problem for industrialization.
(발명의 개시)(Initiation of invention)
본 발명자들은, 그와 같은 문제점에 비추어 예의 검토를 행한 결과, 다음식(I)MEANS TO SOLVE THE PROBLEM The present inventors earnestly examined in view of such a problem, and, as a result, following Formula (I)
(식중, Y는 -CH2-CH2- 또는 -CH=CH=이다.)Wherein Y is -CH 2 -CH 2 -or -CH = CH =.
로 표시되는 프탈이미드 화합물 및 그 산부가염이 상기의 중간체(IX)의 제조에 매우 유용한 것을 발견하고 본 발명에 도달하였다. 즉 본 발명은, 다음식(I)Phthalimide compounds and acid addition salts thereof are found to be very useful for the preparation of the intermediate (IX), and the present invention was reached. That is, the present invention is the following formula (I)
(식중, Y는 -CH2-CH2- 또는 -CH=CH-이다.)Wherein Y is -CH 2 -CH 2 -or -CH = CH-.
로 표시되는 프탈이미드 화합물 및 그 산부가염 및 다음식(II)Phthalimide compound and its acid addition salt represented by the following formula (II)
로 표시 되는 2-클로로-4-(1-피페리디닐메틸) 피리딘과 다음식 (II)2-chloro-4- (1-piperidinylmethyl) pyridine represented by the following formula (II)
HO/＼Y/＼ORHz(II)HO / ＼Y / ＼ORH z (II)
(식중, Y는-CH2-CH2-또는-CH=CH-이고, R은 테트라히드로피란일기, 메톡시메틸기, 트리메틸시릴기 또는 벤질기이다.)(Wherein Y is —CH 2 —CH 2 —or —CH═CH—, and R is tetrahydropyranyl, methoxymethyl, trimethylsilyl or benzyl).
로 표시되는 알코올유도체를 반응시켜서 다음식(IV)By reacting the alcohol derivative represented by the following formula (IV)
(식중, Y는-CH2-CH2-또는-CH=CH-이고, R은 테트라히드로피란일기, 메톡시메틸기, 트리메틸시릴기 또는 벤질기이다.)(Wherein Y is —CH 2 —CH 2 —or —CH═CH—, and R is tetrahydropyranyl, methoxymethyl, trimethylsilyl or benzyl).
로 표시되는 피리딜옥시유도체로 하고, 그 수산기의 보호기 R을 탈보호시켜서 다음식(V)It was made into the pyridyloxy derivative represented by the following, deprotection of protecting group R of the hydroxyl group, and is represented by following formula (V)
(식중, Y는 -CH2-CH2- 또는 -CH=CH-이다.) Wherein Y is -CH 2 -CH 2 -or -CH = CH-.
로 표시되는 피리딜옥시유도체로 하고, 이것을 할로겐화 또는 술포닐화해서 다음식(VI)It was made into the pyridyloxy derivative represented by the following, Halogenated or sulfonylated, and following Formula (VI)
(식중, Y는 -CH2-CH2- 또는 -CH=CH-이고, X는 C1-, Br-, CH3SO3-, CF3SO3- 또는 p-CH3-C6H4-SO3- 이다.)Wherein Y is -CH 2 -CH 2 -or -CH = CH-, X is C1-, Br-, CH 3 SO 3- , CF 3 SO 3 -or p-CH 3 -C 6 H 4- SO 3 -is.)
로 표시되는 피리딜옥시유도체로 한 후, 프탈이미드화하고, 또 필요에 따라서 산과 반응시키는 것을 특징으로 하는 다음식( I )After the pyridyloxy derivative is represented by the following formula, it is phthalimide and reacted with an acid as necessary.
로 표시되는 프탈이미드 화합물 및 그 산부가염의 제조방법이다.It is a manufacturing method of the phthalimide compound represented by this, and its acid addition salt.
본 발명에 있어서, 상기 식(I)로 표시되는 프탈이미드 화합물은, 점성황색오일 형상물이고, 구체적으로는 N-(4-(4-l-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐일) 프탈이미드, N-(4-(4-1-피페리디닐메틸)피리딜-2-옥시)-trans-2-부텐일) 프탈이미드 및 N-(4-(4-(1-피페리디닐메틸)피리딜-2-옥시) 부틸) 프탈이미드이다.In the present invention, the phthalimide compound represented by the formula (I) is a viscous yellow oil, specifically N- (4- (4-l-piperidinylmethyl) pyridyl-2-oxy) -cis-2-butenyl) phthalimide, N- (4- (4-1-piperidinylmethyl) pyridyl-2-oxy) -trans-2-butenyl) phthalimide and N- (4 -(4- (1-piperidinylmethyl) pyridyl-2-oxy) butyl) phthalimide.
본 발명에 있어서의 상기 식(I)로 표시되는 프탈이미드 화합물은, 예를 들면, 이하에 표시한 공정에 따라서 제조가능하다.The phthalimide compound represented by said formula (I) in this invention can be manufactured, for example according to the process shown below.
[제l공정][Step 1]
(식중, Y는-CH2-CH2-또는-CH=CH-이고, R은테트라히드로피란일기, 메톡시메틸기, 트리메틸실릴기 또는 벤질기이다.)(Wherein Y is —CH 2 —CH 2 —or —CH═CH—, and R is a tetrahydropyranyl group, a methoxymethyl group, a trimethylsilyl group, or a benzyl group.)
본 공정은, 상기 식(II)로 표시되는 2-클로로-4-(1-피페리디닐메틸)피리딘과 상기 식(III)으로 표시되는 알코올유도체를 반응시켜, 상기 식(IV)로 표시되는 피리딜옥시유도체를 제조하는 공정이다.In this step, 2-chloro-4- (1-piperidinylmethyl) pyridine represented by the formula (II) is reacted with the alcohol derivative represented by the formula (III), and the compound represented by the formula (IV) It is a process of manufacturing a pyridyloxy derivative.
반응은, 2-클로로-4-(1-피페리디닐메틸)피리딘 1몰에 대해서 알코올유도체를 1몰의 비율로 사용, 나트륨, 수소화나트륨, 칼륨, 수소화칼륨, 리튬, 수소화리튬, n-부틸리튬, sec-부틸리튬, tert-부틸리튬, tert-부톡시칼륨 등의 존재하에서 행하고, 그 사용량은 기질(基質)에 대해서 1∼3당량인 것이 바람직하다. 반응은 용매속에서 행하는 것이 바람직하고, 테트라히드로푸란, 에테르, 디옥산, 벤젠, 톨루엔, 디메틸포름아미드등을 사용할 수 있다. 또, 반응온도는, 20∼l20℃에서 행하는 것이 바람직하다.The reaction was carried out using 1 mole of alcohol derivative per 1 mole of 2-chloro-4- (1-piperidinylmethyl) pyridine, sodium, sodium hydride, potassium, potassium hydride, lithium, lithium hydride, n-butyl In the presence of lithium, sec-butyllithium, tert-butyllithium, tert-butoxy potassium and the like, the amount thereof is preferably 1 to 3 equivalents based on the substrate. It is preferable to perform reaction in a solvent, and tetrahydrofuran, ether, dioxane, benzene, toluene, dimethylformamide, etc. can be used. Moreover, it is preferable to perform reaction temperature at 20-1100 degreeC.
[제2공정][Step 2]
(식중, Y는-CH2-CH2-또는-CH=CH-이고, R은 테트라히드로피란일기, 메톡시메틸기, 트리메틸실릴기 또는 벤질기이다.)(Wherein Y is —CH 2 —CH 2 —or —CH═CH—, and R is a tetrahydropyranyl group, methoxymethyl group, trimethylsilyl group, or benzyl group.)
본 공정은. 상기 식(IV)로 표시되는 피리딜옥시유도체의 수산기의 보호기 R을 탈보호시켜 상기 식(V)로 표시되는 피리딜옥시유도체를 제조하는 공정이다.This process is. It is a process of manufacturing the pyridyloxy derivative represented by said Formula (V) by deprotecting protecting group R of the hydroxyl group of the pyridyloxy derivative represented by said Formula (IV).
반응은, 염산, 황산, 아세트산, p-톨루엔술폰산, p-톨루엔술폰산 피리딘염 등의 산촉매의 존재하에서 행하고, 그 사용량은 기질에 대해서 0.l∼3당량인 것이 바람직하다. 반응은 용매속에서 행하는 것이 바람직하고, 메탄올, 에탄올 등의 알코올류, 아세톤-수, 테트라히드로프판-수, 물 등을 사용할 수 있다. 또, 반응온도는 0∼80℃에서 행하는 것이 바람직하다.The reaction is carried out in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, and p-toluenesulfonic acid pyridine salt, and the amount thereof is preferably 0.1 to 3 equivalents based on the substrate. It is preferable to perform reaction in a solvent, Alcohol, such as methanol and ethanol, acetone-water, tetrahydropropane-water, water, etc. can be used. Moreover, it is preferable to perform reaction temperature at 0-80 degreeC.
[제3공정][Step 3]
(식중, Y는 -CH2-CH2- 또는 -CH=CH-이고, X는 Cl-,Br-,CH3SO3-,CF3SO3- 또는 p-CH3-C6H4-SO3-이다.)Wherein Y is -CH 2 -CH 2 -or -CH = CH-, X is Cl-, Br-, CH 3 SO 3- , CF 3 SO 3 -or p-CH 3 -C 6 H 4- SO 3 -is.)
본 공정은, 상기 식(V)로 표시되는 피리딜옥시유도체를 할로겐화 또는 술포닐화하고, 상기 식(VI)으로 표시되는 피리딜옥시유도체를 제조하는 공정이다.This process is a process of halogenating or sulfonylating the pyridyloxy derivative represented by said Formula (V), and manufacturing the pyridyloxy derivative represented by said Formula (VI).
반응은, 염화티오닐, 염화 p-톨루엔술포닐, 염화메틸술포닐, 염화트리플루오로 메탄술포닐, 4염화탄소-트리페닐포스핀, 4브롬화탄소-트리페닐포스핀등의 존재하에서 행하고, 그 사용량은 기질에 대해서 1∼3당량인것이 바람직하다. 또, 반응에는 염기를 사용하는 것이 바람직하고, 트리에틸아민, 피리딘, 탄산칼륨, 탄산나트륨 등을 사용할 수 있고, 그 사용량은 기질에 대해서 l∼3당량인 겻이 바람직하다. 반응은 용매속에서 행하는 것이 바람직하고, 디클로로메탄, 클로로포름, 벤젠, 톨루엔, 아세트산 에틸, 디메틸포름아미드등을 사용할수 있다. 또, 반응온도는 0∼30℃에서 행하는 것이 바람직하다.The reaction is carried out in the presence of thionyl chloride, p-toluenesulfonyl chloride, methylsulfonyl chloride, trifluoro methanesulfonyl chloride, carbon tetrachloride-triphenylphosphine, carbon tetrabromide-triphenylphosphine, and the like. It is preferable that the usage-amount is 1-3 equivalents with respect to a board | substrate. Moreover, it is preferable to use a base for reaction, and triethylamine, pyridine, potassium carbonate, sodium carbonate, etc. can be used, The amount of the use is preferably 1-3 equivalents with respect to a board | substrate. It is preferable to perform reaction in a solvent, and dichloromethane, chloroform, benzene, toluene, ethyl acetate, dimethylformamide, etc. can be used. Moreover, it is preferable to perform reaction temperature at 0-30 degreeC.
[제4공정][Step 4]
(식중, Y는 -CH2-CH2- 또는 -CH=CH-이고, X는 C1-,Br-,CH3SO3-,CF3SO3- 또는 p-CH3-C6H4-SO3-이다.)Wherein Y is -CH 2 -CH 2 -or -CH = CH-, X is C1-, Br-, CH 3 SO 3- , CF 3 SO 3 -or p-CH 3 -C 6 H 4- SO 3 -is.)
본 공정은, 상기 식(VI)으로 표시되는 피리딜옥시유도체를 프탈이미드화하고, 상기 식(I)로 표시되는 프탈이미드 화합물을 제조하는 공정이다.This step is a step of phthalimating the pyridyloxy derivative represented by the formula (VI) to produce a phthalimide compound represented by the formula (I).
반응은, 피리딜옥시유도체 1몰에 대해서 프탈이미드칼륨을 1몰 사용해서 행하나, 상간(相間) 이동촉매의 존재하에 반응시키면 신속하게 반응을 완결시킬 수 있다. 상간 이동촉매로서는 황산수소테트라-n-부틸암모늄, 염화테트라-n-부틸암모늄, 브롬화테트라-n-부틸암모늄 등을 사용할 수 있고, 그 사용량은 기질에 대해서 0.01∼3당량인 것이 바람직하다. 반응은 용매속에서 행하는 것이 바람직하고, 벤젠, 톨루엔, 아세토니트릴, 아세트산에틸둥을 사용할 수 있다. 또, 반응온도는 0∼10O℃에서 행하는 것이 바람직하다.The reaction is carried out using 1 mole of phthalimide potassium per 1 mole of pyridyloxy derivative, but the reaction can be completed quickly by reacting in the presence of a phase transfer catalyst. As the phase transfer catalyst, tetrahydrogen tetra-n-butylammonium sulfate, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide and the like can be used, and the amount thereof is preferably 0.01 to 3 equivalents based on the substrate. It is preferable to perform reaction in a solvent, and benzene, toluene, acetonitrile, ethyl acetate can be used. Moreover, it is preferable to perform reaction temperature at 0-10 degreeC.
이상과 같이 해서 상기 식(I)로 표시되는 프탈이미드 화합물을 제조할 수 있다.As described above, the phthalimide compound represented by the formula (I) can be produced.
또, 상기 식(I)로 표시되는 프탈이미드 화합물은, 상법에 따라서 산부가염으로 할 수가 있고, 고체로서 단리할 수가 있다. 산으로서는, 염산, 브롬화수소산, 질산, 황산, 옥살산, 숙신산, 말레산, 푸마르산, 타르타르산, 젖산, 프탈산등을 사용할 수 있다. 프탈이미드 화합물의 산부가염으로서는, 구체적으로는 N-(4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐일)프탈이미드·2염산·에탄올염, N-(4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐일)프탈이미드·2질산염, N-(4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐일)프탈이미드·말레산염, N-(4-(4-(1-피페리디닐메틸)피리딜-2-옥시)부틸)프탈이미드1·푸마르산염 등을 예시할 수 있다. 이 프탈이미드 화합물의 산부가염은, 재결정법에 의해 정제가능하다.Moreover, the phthalimide compound represented by said Formula (I) can be made into acid addition salt according to a conventional method, and can be isolated as a solid. As the acid, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, oxalic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, lactic acid, phthalic acid and the like can be used. As an acid addition salt of a phthalimide compound, N- (4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) -cis-2-butenyl) phthalimide dihydrochloric acid specifically, Ethanol salt, N- (4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) -cis-2-butenyl) phthalimide dinitrate, N- (4- (4- ( 1-piperidinylmethyl) pyridyl-2-oxy) -cis-2-butenyl) phthalimide maleate, N- (4- (4- (1-piperidinylmethyl) pyridyl-2- Oxy) butyl) phthalimide 1, fumarate, etc. can be illustrated. The acid addition salt of this phthalimide compound can be refine | purified by the recrystallization method.
상기 식(I)로 표시되는 프탈이미드 화합물 및 그 산부가염은, 프탈로일기의 탈보호에 의해 용이하게 상기 식(IX)로 표시되는 아민체로 변환할 수 있어, 상기의 중간체(IX)의 제조에 유용한 화합물이다. 특히 프탈이미드 화합물의 산부가염은, 재결정법에 의해 용이하게 정제가능하므로서 변환 후의 상기의 식(IX)로 표시되는 아민체의 순도를 용이하게 향상시킬 수 있고, 또, 그것에 의해서 아민체(IX)로부터 유도되는 상기의 식(VII)이나 식(VIII)등으로 표시되는 항궤양제의 순도의 향상에도 기여할 수 있어, 매우 유용한 화합물이다.The phthalimide compound represented by the said Formula (I) and its acid addition salt can be easily converted into the amine body represented by the said Formula (IX) by deprotection of a phthaloyl group, and of the said intermediate (IX) Useful compound for preparation. In particular, the acid addition salt of the phthalimide compound can be easily purified by a recrystallization method, so that the purity of the amine represented by the above-described formula (IX) after conversion can be easily improved, whereby the amine (IX It is a very useful compound which can contribute to the improvement of the purity of the antiulcer agent represented by Formula (VII), Formula (VIII) and the like derived from
(실시예)(Example)
이하, 실시예에 의해 본 발명을 구체적으로 설명한다.Hereinafter, an Example demonstrates this invention concretely.
(실시예1)Example 1
수소화나트륨(60%순도,4.56g)을 테트라히드로푸란(100㎖) 및 디메틸포름아미드(5㎖)에 현탁시키고, 빙냉하, 상기 식(II)로 표시되는 2-클로로-4-(1-피페리디닐메틸)피리딘(l5.0g) 및 상기 식(XIII)으로 표시되는 4-(2-옥시테트라히드로피란일) -cis-2-부텐-1-올(l2.3g)을 적하한 후, 서서히 실온까지 온도를 올리고, 더 온도를 올려서 11시간 환류하였다. 냉각후, 물을 첨가, 아세트산에틸에 의해 추출하고, 물, 포화식염수로 세정하고, 무수황산마그네슘으로 건조후, 여과하고, 용매를 증류제거해서, 실리카겔컬럼크로마토그래피에 의해 정제하고, 상기식(XIV)로 표시되는 2-(4-(2-옥시테트라히드로피란일)-cis-2-부텐-1-옥시)-4-(1-피페리디닐메틸)피리딘(22 .5g,91.3%)을 얻었다.Sodium hydride (60% purity, 4.56 g) is suspended in tetrahydrofuran (100 mL) and dimethylformamide (5 mL), and under ice-cooling, 2-chloro-4- (1-) represented by the formula (II). Piperidinylmethyl) pyridine (l5.0 g) and 4- (2-oxytetrahydropyranyl) -cis-2-buten-1-ol (l2.3 g) represented by the formula (XIII) were added dropwise thereto. The temperature was gradually raised to room temperature, and the temperature was further raised to reflux for 11 hours. After cooling, water was added, extraction was performed with ethyl acetate, the mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off and purified by silica gel column chromatography. 2- (4- (2-oxytetrahydropyranyl) -cis-2-butene-1-oxy) -4- (1-piperidinylmethyl) pyridine represented by XIV) (22 .5 g, 91.3%) Got.
(실시예2)Example 2
상기 식(XIV)로 표시되는 2-(4-(2-옥시테트라히드로피란일) -cis-2-부텐-1-옥시)-4-(1-피페리디닐메틸)피리딘(22.5g) 을 아세트산에틸(100㎖)에 용해하고, lN -HC1(100㎖)을 첨가, 실온에서 2시간 교반하였다. 반응종료후, 물층을 분리하고, 아세트산에틸로 세정후, 탄산칼륨에 의해 알칼리성으로 하고, 디클로로메탄에 의해 추출하여, 포화식염수로 세정하고, 무수황산마그네슘에 의해 건조후, 여과하고, 용매를 증류제거해서 상기식(XV)로 표시되는 4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐-1-올(l5.5g,91.0%)을 얻었다.2- (4- (2-oxytetrahydropyranyl) -cis-2-butene-1-oxy) -4- (1-piperidinylmethyl) pyridine (22.5 g) represented by the formula (XIV) It dissolved in ethyl acetate (100 mL), added lN-HC1 (100 mL), and stirred at room temperature for 2 hours. After completion of the reaction, the water layer was separated, washed with ethyl acetate, made alkaline with potassium carbonate, extracted with dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off. Removing to obtain 4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) -cis-2-buten-1-ol (l5.5 g, 91.0%) represented by the formula (XV). .
IR(cm-1, film) 3370, 2935, 1614IR (cm -1 , film) 3370, 2935, 1614
1H-NMR(,CDCl3)1.30∼1.75(6H,m), 2.23∼2.52(4H,m), 3.40(2H,s), 3.49(lH,bs), 4.32(2H,d,J=6Hz), 4.99(2H,d,J=6Hz), 5.57∼6.09(2H,m), 6.74(lH,s), 6.89(lH,d,J=5Hz), 8.01(lH,d,J=5Hz) 1 H-NMR ( , CDCl 3 ) 1.30 to 1.75 (6H, m), 2.23 to 2.52 (4H, m), 3.40 (2H, s), 3.49 (lH, bs), 4.32 (2H, d, J = 6 Hz), 4.99 (2H , d, J = 6 Hz, 5.57 to 6.09 (2H, m), 6.74 (lH, s), 6.89 (lH, d, J = 5 Hz), 8.01 (lH, d, J = 5 Hz)
(실시예3)Example 3
상기식(XV)로 표시되는 4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐-1-올(15.5g)을 디클로로메탄(200㎖)에 용해하고, 무수탄산칼륨(9.4g)을 현탁시키고, 빙냉하, 염화티오닐(10.2g)의 디클로로메탄(20㎖l)용액을 적하하고, 서서히 실온까지 온도를 올려 2시간 교반하였다. 반응종료후, 5% 탄산수소나트륨 수용액을 첨가, 유기층을 분리하고, 1.5N-HCI에 의해 추출하고, 톨루엔으로 세정후, 탄산칼륨에 의해 알칼리성으로 하고, 톨루엔으로 추출해서, 포화식염수로 세정하고 무수황산마그네슘에 의해 건조후, 여과해서 상기식(XVI)으로 표시되는 1-클로로-4-(4-(l-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐(14.7g,88.6%)을 함유한 톨루엔용액(80㎖)을 얻었다.4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) -cis-2-buten-1-ol (15.5 g) represented by the formula (XV) was added to dichloromethane (200 mL). It melt | dissolved, anhydrous potassium carbonate (9.4g) was suspended, the ice-cooled dichloromethane (20 mL) solution of thionyl chloride (10.2g) was dripped, and the temperature was gradually raised to room temperature, and it stirred for 2 hours. After completion of the reaction, 5% aqueous sodium hydrogen carbonate solution was added, the organic layer was separated, extracted with 1.5N-HCI, washed with toluene, alkaline with potassium carbonate, extracted with toluene and washed with saturated brine. 1-chloro-4- (4- (l-piperidinylmethyl) pyridyl-2-oxy) -cis-2-butene (14.7 represented by the formula (XVI) after filtration with anhydrous magnesium sulfate was filtered. g, 88.6%) toluene solution (80 ml) was obtained.
(실시예4)Example 4
상기 식(XVI)으로 표시되는 1-클로로-4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐(l4.7g)을 함유한 톨루엔용액(80㎖)에, 상기 식(XII)로 표시되는 프탈이미드칼륨(13.2g), 황산수소테트라-n-부틸암모늄(1.45g)을 현탁시키고, 80℃에서 2시간 반응시켰다. 냉각후, 반응액을 1N-NaOH로 세정하고, 포화식염수로 세정해서, 무수황산마그네슘에 의해 건조후, 여과하고, 용매를 증류제거해서 상기 식(XVII)로 표시되는 N-(4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐일)프탈이미드(18.0g,87.8%)를 얻었다.Toluene solution containing 1-chloro-4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) -cis-2-butene (l4.7 g) represented by the formula (XVI) (80) (Ml) was suspended in phthalimide potassium (13.2 g) and tetrahydrogen tetra-n-butylammonium sulfate (1.45 g) represented by the above formula (XII) and reacted at 80 ° C for 2 hours. After cooling, the reaction solution was washed with 1N-NaOH, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain N- (4- (4) represented by the formula (XVII). -(1-piperidinylmethyl) pyridyl-2-oxy) -cis-2-butenyl) phthalimide (18.0 g, 87.8%) was obtained.
IR(cm-1, film) 2935, 1770, 1714, 1615IR (cm -1 , film) 2935, 1770, 1714, 1615
1H-NMR(,CDCl3)1.30∼1.75(6H,m), 2.23∼2.52(4H,m), 3.41(2H,s), 4.47(2H,d,J=6Hz), 5.12(2H,d,J=6H2, 5.50~6.15(2H,m), 6.75(1H,s), 6.89(2H,d,J=5Hz), 7.65~7.97(4H,m), 8.08(2H,d,J=5Hz) 1 H-NMR ( , CDCl 3 ) 1.30 to 1.75 (6H, m), 2.23 to 2.52 (4H, m), 3.41 (2H, s), 4.47 (2H, d, J = 6 Hz), 5.12 (2H, d, J = 6H 2 , 5.50 ~ 6.15 (2H, m), 6.75 (1H, s), 6.89 (2H, d, J = 5Hz), 7.65 ~ 7.97 (4H, m), 8.08 (2H, d, J = 5Hz)
(실시예5)Example 5
상기 식(XVIII)로 표시되는 N-(4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐일)프탈이미드(3.29g)를 에탄올(30㎖)에 용해하고, 이것에 염화수소가스를 통해서 빙냉시켰다. 석출된 백색결정을 여과하여, 에탄올-n-핵산으로 세정하고, 건조해서 상기식(XVIII)로 표시되는 N-(4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐일)프탈이미드·2염산·에탄올염(3.70g,86.2%)를 얻었다.N- (4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) -cis-2-butenyl) phthalimide (3.29 g) represented by the formula (XVIII) was added to ethanol (30 ML) and ice-cooled through hydrogen chloride gas. The precipitated white crystals were filtered off, washed with ethanol-n-nucleic acid, dried and N- (4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) represented by the formula (XVIII). -cis-2-butenyl) phthalimide dihydrochloric acid and ethanol salt (3.70 g, 86.2%) were obtained.
m.p. 155∼l701℃(분해)m.p. 155 to l701 ° C (decomposition)
1R(cm-1,KBr) 3408, 2948, 2632, 2532, l768, 1714, 1616, 1394, 12941R (cm -1 , KBr) 3408, 2948, 2632, 2532, l768, 1714, 1616, 1394, 1294
1H-NMR(,DMSO-d6) 1.06(3H,t,J=7Hz), 1.29∼1.42(1H.m) ,l.67∼1.94(5H,m), 2.80∼2.91(2H,m), 3.28(2H,d,J=12Hz), 3.45(2H,q,J=7Hz), 4.26(2H,d,J=6Hz), 4 .36(2H,d,J=7Hz), 5.05(2H,d,J=6Hz), 5.62∼5.71(1H,m),5.80∼5.89(1H,m), 7.18(1H,s), 7.32(1H,d,J=6Hz), 7.82∼7.91(4H,m), 8.25(1H,d,J=6Hz), 11.20(1H,broad) 1 H-NMR ( DMSO-d 6 ) 1.06 (3H, t, J = 7 Hz), 1.29-1.42 (1 H.m), l.67-1.94 (5H, m), 2.80-2.91 (2H, m), 3.28 (2H, d, J = 12 Hz, 3.45 (2H, q, J = 7 Hz), 4.26 (2H, d, J = 6 Hz), 4.36 (2H, d, J = 7 Hz), 5.05 (2H, d, J = 6 Hz), 5.62 to 5.71 (1H, m), 5.80 to 5.89 (1H, m), 7.18 (1H, s), 7.32 (1H, d, J = 6 Hz), 7.82 to 7.91 (4H, m), 8.25 ( 1H, d, J = 6Hz), 11.20 (1H, broad)
(실시예6)Example 6
상기식(XVIII)로 표시되는 N-(4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐일)프탈이미드(2.25g)를 에탄올(30㎖)에 용해하고, 이것에 농질산(61% 순도,1.3㎖)을 첨가, 냉장고에서 2일간 냉각하였다. 석출된 결정을 여과하고, 건조해서 상기 식(XIX)으로 표시되는 N-(4-(4-(1-피페리딜메틸)피리딜-2-옥시) -cis-2-부텐일)프탈이미드·2질산염(2.70g,90.7%)을 얻었다.N- (4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) -cis-2-butenyl) phthalimide (2.25 g) represented by the formula (XVIII) was added to ethanol (30 ML), and concentrated nitric acid (61% purity, 1.3 mL) was added thereto, followed by cooling in a refrigerator for 2 days. The precipitated crystals were filtered, dried and N- (4- (4- (1-piperidylmethyl) pyridyl-2-oxy) -cis-2-butenyl) phthal represented by the formula (XIX) Mid dinitrate (2.70 g, 90.7%) was obtained.
m.p. l14∼116℃(분해)m.p. 14 to 116 ° C (decomposition)
IR(cm-1,KBr) 2944, 2636, 1770, l714, 1642, 1394, 1280IR (cm -1 , KBr) 2944, 2636, 1770, l714, 1642, 1394, 1280
1H-NMR(,DMSO-d6) 1.30∼2.00(6H,m), 2.65∼3.20(2H,m), 3.20∼3.55(2H,m), 4.36(2H.s), 4.38(2H,d,J=6Hz), 5.10(2H,d,J=6Hz), 5.55∼6.05(2H,m),7.06(lH,s), 7.19(lH,d,J=5Hz), 7.91(4H,s), 8.32(lH,d,J=5Hz), 8.53(2H,bs) 1 H-NMR ( DMSO-d 6 ) 1.30 to 2.00 (6H, m), 2.65 to 3.20 (2H, m), 3.20 to 3.55 (2H, m), 4.36 (2H.s), 4.38 (2H, d, J = 6Hz) , 5.10 (2H, d, J = 6 Hz), 5.55-6.05 (2H, m), 7.06 (lH, s), 7.19 (lH, d, J = 5 Hz), 7.91 (4H, s), 8.32 (lH, d, J = 5 Hz), 8.53 (2H, bs)
(실시예7)Example 7
상기 식(XVIII)로 표시되는 N-(4-(4-(1-피페리디닐메틸)피리딜-2-옥시) -cis-2-부텐일)프탈이미드(3.33g)를 에탄올(35㎖)에 용해하고, 이것에 말레산(l.09g)을 첨가, 2시간 빙냉하였다. 석출된 백색결정을 여과하고, 건조해서 상기 식(XX)으로 표시되는 N-(4-(4-(l-피페리디닐메틸)피리딜-2-옥시)-cis-2-부텐일)프탈이미드·말레산염(4.00g,92. 6%)을 얻었다.N- (4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) -cis-2-butenyl) phthalimide (3.33 g) represented by the formula (XVIII) was added to ethanol (35 Ml), and maleic acid (l.09 g) was added thereto, followed by ice cooling for 2 hours. Precipitated white crystals were filtered, dried and N- (4- (4- (l-piperidinylmethyl) pyridyl-2-oxy) -cis-2-butenyl) phthal represented by the formula (XX). Imide maleate (4.00 g, 99.6%) was obtained.
m.p. l48∼150℃(분해)m.p. 48 to 150 ° C (decomposition)
IR(cm-1,KBr) 3468, 2940, 2536, 1770, 17l0, 1620, 1568, 1456, 1392, 1066, 990, 874, 718IR (cm -1 , KBr) 3468, 2940, 2536, 1770, 17l0, 1620, 1568, 1456, 1392, 1066, 990, 874, 718
1H-NMR(,DMSO-d6) l.36∼1.93(6H,m), 2.90∼3.20(4H,m), 4.23(2H,s), 4.39(2H,d,J=6Hz), 5.09(2H,d,J=6Hz), 5.55∼6.00(2H,m), 6.12(2H,s), 7.02(1H,s), 7.16(1H,d,J=5Hz), 7.92(4H,s), 8.31(1H,d,J=5Hz) 1 H-NMR ( , DMSO-d 6 ) l.36-1.93 (6H, m), 2.90-3.20 (4H, m), 4.23 (2H, s), 4.39 (2H, d, J = 6 Hz), 5.09 (2H, d, J = 6 Hz), 5.55-6.00 (2H, m), 6.12 (2H, s), 7.02 (1H, s), 7.16 (1H, d, J = 5 Hz), 7.92 (4H, s), 8.31 (1H, d, J = 5 Hz)
(실시예8)Example 8
수소화나트륨(60% 순도,13.29g)을 테트라히드로푸란(250㎖) 및 디메틸포름아미드(15㎖)에 현탁시키고, 빙냉하, 상기 식(II)로 표시되는 2-클로로-4-(1-피페리디닐메틸)피리딜(50.0g) 및 상기 식(XXI)로 표시되는 4-(2-옥시테트라히드로피라닐)-부탄-1-올(41.4g)을 적하한 후, 서서히 실온까지 온도를 올리고, 또 온도를 올려서 15시간 환류하였다. 냉각후, 물을 첨가, 아세트산에틸로 추출하고, 물, 포화식염수로 세정하고, 무수황산마그네슘에 의해 건조후, 여과하고, 용매를 증류제거하고, 실리카겔컬럼크로마토그래피에 의해 정제하고, 상기식(XXII)로 표시되는 2-(4-2-옥시테트라히드로피라닐)-부탄-1-옥시)-4-(1-피페리디닐메틸)피리딜(74.5g,90.%)을 얻었다.Sodium hydride (60% purity, 13.29 g) is suspended in tetrahydrofuran (250 mL) and dimethylformamide (15 mL) and under ice-cooling, 2-chloro-4- (1- Piperidinylmethyl) pyridyl (50.0 g) and 4- (2-oxytetrahydropyranyl) -butan-1-ol (41.4 g) represented by the above formula (XXI) were added dropwise, followed by gradually increasing the temperature to room temperature. The temperature was raised to reflux for 15 hours. After cooling, water was added, extraction was performed with ethyl acetate, the mixture was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off and purified by silica gel column chromatography. 2- (4-2-oxytetrahydropyranyl) -butane-1-oxy) -4- (1-piperidinylmethyl) pyridyl (74.5 g, 90.%) represented by XXII) was obtained.
(실시예9)Example 9
상기 식(XX1I)로 표시되는 2-(4-(2-옥시테트라히드로피라닐)-부탄-1-옥시)-4-(1-피페리디닐메틸)피리딜(74.5g)을 아세트산에틸(400㎖)에 용해하고, lN-HCl(340㎖)을 첨가해서 실온에서 12시간 교반하였다. 반응종료후, 물층을 분리하고, 아세트산에틸로 세정후, 탄산칼륨으로 알칼리성으로 하고, 아세트산에틸로 추출하고, 포화식염수로 세정하고, 무수황산마그네슘으로 건조후, 여과해서, 용매를 증류제거해서 상기식(XXIII)으로 표시되는 4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-1-부탄-1-올(50.4g,89.2%)을 얻었다.2- (4- (2-oxytetrahydropyranyl) -butane-1-oxy) -4- (1-piperidinylmethyl) pyridyl (74.5 g) represented by the formula (XX1I) was substituted with ethyl acetate ( 400 mL), 1N-HCl (340 mL) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the water layer was separated, washed with ethyl acetate, made alkaline with potassium carbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off. 4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) -1-butan-1-ol (50.4 g, 89.2%) represented by formula (XXIII) was obtained.
1H-NMR(,CDC13) 1.00∼2.04(10H,m), 2.12∼2.52(4H,m), 2.75(1H,broad), 3.41(2H,s), 3.71(2H,t,J=6Hz), 4,31(2H,t,J=6Hz), 6.71(1H,s), 6.85(1H,d,J=5Hz), 8 .03(1H,d,J=5Hz) 1 H-NMR ( , CD1 3 ) 1.00 ~ 2.04 (10H, m), 2.12 ~ 2.52 (4H, m), 2.75 (1H, broad), 3.41 (2H, s), 3.71 (2H, t, J = 6Hz), 4,31 (2H, t, J = 6Hz), 6.71 (1H, s), 6.85 (1H, d, J = 5Hz), 8 .03 (1H, d, J = 5Hz)
(실시예10)Example 10
상기 식(XXIII)으로 표시되는 4-(4-(l-피페리디닐메틸)피리딜-2-옥시)-부탄-1-올(50.0g)을 디클로로메탄(500㎖)에 용해하고, 트리에틸아민(47.8g)을 첨가, 빙냉하, 메탄술포닐클로라이드(36.8g)를 적하하고, 서서히 실온까지 온도를 올리고, 1시간 교반하였다. 반응종료후, 5% 탄산수소나트륨수용액을 첨가, 유기층을 분리하고, 무수황산마그네슘으로 건조후, 여과하고, 용매를 증류제거해서 상기 식(XXIV)로 표시되는 l-메탄술포닐옥시-4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-부탄(58.5g,94.8%)을 얻었다.4- (4- (l-piperidinylmethyl) pyridyl-2-oxy) -butan-1-ol (50.0 g) represented by the above formula (XXIII) was dissolved in dichloromethane (500 mL), and Ethylamine (47.8 g) was added, methanesulfonyl chloride (36.8 g) was dripped under ice-cooling, and it heated up to room temperature gradually and stirred for 1 hour. After completion of the reaction, 5% aqueous sodium hydrogen carbonate solution was added, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to yield l-methanesulfonyloxy-4- represented by the formula (XXIV). (4- (1-piperidinylmethyl) pyridyl-2-oxy) -butane (58.5 g, 94.8%) was obtained.
1H-NMR(,CDCl3) 1.09∼l.75(6H,m), 1.75∼2.10(4H,m), 2.16∼2.53(4H,m), 3.02(3H,s), 3.41(2H,s), 4.04∼4.48(4H,m), 6.71(1H,s), 6.86(1H,d,J=5Hz), 8.03(1H,d,J=5Hz) 1 H-NMR ( , CDCl 3 ) 1.09 to 1.75 (6H, m), 1.75 to 2.10 (4H, m), 2.16 to 2.53 (4H, m), 3.02 (3H, s), 3.41 (2H, s), 4.04 to 4.48 (4H, m), 6.71 (1H, s), 6.86 (1H, d, J = 5 Hz), 8.03 (1H, d, J = 5 Hz)
(실시예11)Example 11
상기 식(XXIV)로 표시되는 1-메탄술포닐옥시-4-(4-(1-피페리디닐메틸)피리딜-2-옥시)-부탄(58.5g)을 아세트니트릴(40㎖)에 용해하고, 상기 식(XII)로 표시되는 프탈이미드칼륨(52.6g), 황산수소테트라-n-부틸암모늄(3.9g)을 현탁시키고, 5시간 환류하였다. 냉각후, 반응액을 여과하고, 용매를 증류제거하였다. 잔사를 아세트산에틸에 용해하고, lN-NaOH에서 세정하고, 포화식염수로 세정하고, 무수황산마그네슘으로 건조후, 여과하고, 용매를 증류제거해서 상기식(XXV)로 표시되는 N-(4-(4-(l-피페리디닐메틸)피리닐-2-옥시)부틸) 프탈이미드(60.2g,85.4%)를 얻었다.Dissolve 1-methanesulfonyloxy-4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) -butane (58.5 g) represented by the above formula (XXIV) in acetonitrile (40 mL). Potassium phthalimide (52.6 g) and tetrahydrogen tetra-n-butylammonium sulfate (3.9 g) represented by the formula (XII) were suspended and refluxed for 5 hours. After cooling, the reaction solution was filtered and the solvent was distilled off. The residue was dissolved in ethyl acetate, washed with 1N-NaOH, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain N- (4- ( 4- (l-piperidinylmethyl) pyridyl-2-oxy) butyl) phthalimide (60.2 g, 85.4%) was obtained.
m.p. 46∼48℃m.p. 46 ~ 48 ℃
IR(cm-1,film) 2940, 2856, 2796, l772, 1712, 1614, 1560, 1470, 1422, l398, 1372, l044, 720IR (cm -1 , film) 2940, 2856, 2796, l772, 1712, 1614, 1560, 1470, 1422, l398, 1372, l044, 720
1H-NMR(,CDCl3) 1.24∼l.72(6H,m), 1.72∼1.99(4H,m), 2.20∼2.48(4H,m), 3.39(2H,s), 3.60∼3.88(2H,m), 4.14∼4.41(2H,m), 6.67(1H,s), 6.83(1H,d,J=5Hz), 7 .52∼7.92(4H,m), 8.02(1H,d,J=5Hz) 1 H-NMR ( , CDCl 3 ) 1.24 to 1.72 (6H, m), 1.72 to 1.99 (4H, m), 2.20 to 2.48 (4H, m), 3.39 (2H, s), 3.60 to 3.88 (2H, m), 4.14 -4.41 (2H, m), 6.67 (1H, s), 6.83 (1H, d, J = 5 Hz), 7.52-7.72 (4H, m), 8.02 (1H, d, J = 5 Hz)
(실시예12)Example 12
상기 식(XXV)로 표시되는 N-(4-(4-(1-피페리디닐메틸)피리딜-2-옥시)부틸)프탈이미드(0.50g)과 푸마르산(0.37g)을 에탄올(20㎖)에 가열용해하고, 용액량이 약 5㎖가 될때까지 감압하, 농축하여, 빙냉하에 12시간 방치하였다. 석출된 결정을 여과하고, 건조해서 백색결정의 상기 식(XXVI)으로 표시되는 N-(4-(4-(1-피페리디닐메틸)피리딜-2-옥시)부틸)프탈이미드 푸마르산염(0.52g,80.3%)을 얻었다. N- (4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) butyl) phthalimide (0.50 g) and fumaric acid (0.37 g) represented by the above formula (XXV) were added to ethanol (20). ML), and the mixture was heated and dissolved under reduced pressure until the solution amount became about 5 mL, and left for 12 hours under ice cooling. The precipitated crystals were filtered, dried and N- (4- (4- (1-piperidinylmethyl) pyridyl-2-oxy) butyl) phthalimide fumarate represented by the above formula (XXVI) as white crystals. (0.52 g, 80.3%) was obtained.
m.p. 104∼106℃m.p. 104 ~ 106 ℃
IR(cm-1,KBr) 3460, 2948, 2640, 2540, 1768, 1712, 1650, 16l2, l562, 1428, 1398, 1364, l306, 1168, 1058, 984, 714, 646IR (cm -1 , KBr) 3460, 2948, 2640, 2540, 1768, 1712, 1650, 16l2, l562, 1428, 1398, 1364, l306, 1168, 1058, 984, 714, 646
1H-NMR(,DMSO-d6) 1.20∼1.98(10H,m), 2.32∼2.68(4H,m), 3.42∼3.80(2H,s,2H,m), 4.08∼4.40(2H,m), 6.62(2H,s), 6.74(1H,s), 6.93(1H,d,J=5Hz), 7.84(4H,s), 8.05(1H,d,J=5Hz), 9.22(2H,broad) 1 H-NMR ( DMSO-d 6 ) 1.20 to 1.98 (10H, m), 2.32 to 2.68 (4H, m), 3.42 to 3.80 (2H, s, 2H, m), 4.08 to 4.40 (2H, m), 6.62 (2H, s), 6.74 (1H, s), 6.93 (1H, d, J = 5Hz), 7.84 (4H, s), 8.05 (1H, d, J = 5Hz), 9.22 (2H, broad)
[발명의 효과][Effects of the Invention]
본 발명은, 의약품, 특히 히스타민 H2수용체 길항작용에 의거한 항궤양제의 제조중간체로서 유용한 화합물인 상기 식(I)로 표시되는 프탈이미드 화합물 및 그 산부가염을 제공하는 것이다. 특히 프탈이미드 화합물의 산부가염은, 재결정법에 의해 용이하게 정제가능하고, 그에 의해서 본 발명의 프탈이미드 화합물 및 그 산부가염으로부터 유도되는 상기 식(VII)이나 식(VIII)등으로 표시되는 항궤양제의 순도 향상에 기여할 수 있다고 하는 효과를 나타낸다.The present invention provides a phthalimide compound represented by the above formula (I) and an acid addition salt thereof, which are compounds useful as pharmaceutical intermediates, in particular, as intermediates for the preparation of anti-ulcer agents based on histamine H 2 receptor antagonism. In particular, the acid addition salt of the phthalimide compound can be easily purified by a recrystallization method, and is represented by the above formula (VII), formula (VIII), or the like derived from the phthalimide compound and the acid addition salt of the present invention. The effect that it can contribute to the purity improvement of an antiulcer agent is shown.
Claims (17)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP91-10211 | 1991-01-30 | ||
| JP1021191 | 1991-01-30 | ||
| PCT/JP1992/000068 WO1992013854A1 (en) | 1991-01-30 | 1992-01-27 | Phthalimide compound and production thereof |
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| KR930703299A KR930703299A (en) | 1993-11-29 |
| KR0125155B1 true KR0125155B1 (en) | 1997-12-05 |
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| KR1019930702259A KR0125155B1 (en) | 1991-01-30 | 1992-01-27 | Phthalimide compounds and method of producing same |
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| US (1) | US5382589A (en) |
| EP (1) | EP0569587A1 (en) |
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| WO (1) | WO1992013854A1 (en) |
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| CN101747261B (en) * | 2008-12-16 | 2012-02-22 | 浙江东亚药业有限公司 | Method for preparing 4-[4-(1-piperidinyl) pyridine-2-O]-cis-2-butene-1-ol |
| CN102212031B (en) * | 2010-12-31 | 2014-04-09 | 华润双鹤药业股份有限公司 | Preparation method of 2-substituted-4-(piperidylmethyl) pyridine |
| CN102212060A (en) * | 2010-12-31 | 2011-10-12 | 北京双鹤药业股份有限公司 | Method for preparing lafutidine by virtue of aminolysis |
| EP3026047A4 (en) * | 2013-07-25 | 2017-05-17 | Nissan Chemical Industries, Ltd. | Method for producing heterocyclic compound |
| CN104557889B (en) * | 2014-12-15 | 2017-06-16 | 广东东阳光药业有限公司 | The preparation method of Lafutidine isomers |
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| IL69392A (en) * | 1982-08-13 | 1987-01-30 | Sanofi Sa | N-oxide nicotinamide derivatives,their preparation and pharmaceutical compositions containing them |
| JPS6185365A (en) * | 1984-10-02 | 1986-04-30 | Ikeda Mohandou:Kk | Aminoalkylpyridyloxy derivative |
| CA1275097A (en) * | 1984-10-02 | 1990-10-09 | Fujio Nohara | Pyridyloxy derivatives |
| JPS63225371A (en) * | 1987-03-13 | 1988-09-20 | Fujirebio Inc | Pyridyloxy derivative |
| US4912101A (en) * | 1987-03-13 | 1990-03-27 | Fujirebio Kabushiki Kaisha | 4-aminomethyl-pyridyl-2-oxy derivatives having anti-ulcer activity |
| JP2597124B2 (en) * | 1987-12-28 | 1997-04-02 | 広栄化学工業株式会社 | Preparation of pyridinecarboxylic acid esters |
| JPH078857B2 (en) * | 1988-10-31 | 1995-02-01 | 富士レビオ株式会社 | Azide compound |
-
1992
- 1992-01-27 WO PCT/JP1992/000068 patent/WO1992013854A1/en not_active Application Discontinuation
- 1992-01-27 EP EP92903737A patent/EP0569587A1/en not_active Withdrawn
- 1992-01-27 KR KR1019930702259A patent/KR0125155B1/en not_active IP Right Cessation
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| US5382589A (en) | 1995-01-17 |
| EP0569587A4 (en) | 1994-01-05 |
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